Molecular markers of anti-malarial drug resistance in Central, West and East African children with severe malaria

Malaria Journal

Research

Bernhards R. Ogutu¹  Tsiri Agbenyega²  Christian N. Nguetse³  Peter G. Kremsner⁴  Ayola Akim Adegnika⁴  Thirumalaisamy P. Velavan⁵  Sanjeev Krishna⁶ 

[1] Centre for Clinical Research, Kenya Medical Research Institute, Kisumu, Kenya;Department of Physiology, University of Science and Technology, School of Medical Sciences, Kumasi, Ghana;Departments of Child Health and Medicine, Komfo Anokye Teaching Hospital, Kumasi, Ghana;Institute of Tropical Medicine, University Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany;Institute of Tropical Medicine, University Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany;Centre de Recherches Médicales de Lambaréné, Lambaréné, Gabon;Institute of Tropical Medicine, University Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany;Fondation Congolaise pour la Recherche Médicale, Brazzaville, Republic of Congo;Vietnamese-German Center for Medical Research, Hanoi, Vietnam;Faculty of Medicine, Duy Tan University, Da Nang, Vietnam;Institute of Tropical Medicine, University Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany;Institute for Infection and Immunity, St George’s University of London, London, UK;

关键词: Malaria;    P. falciparum;    Pfmdr1;    Pfatp6;    Pfk13;    Anti-malarial drugs;    Resistance;    Africa;   

DOI  :  10.1186/s12936-017-1868-y

 received in 2017-02-02, accepted in 2017-05-17,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundThe Plasmodium falciparum multidrug resistance 1 (PfMDR1), P. falciparum Ca2+-ATPase (PfATP6) and Kelch-13 propeller domain (PfK13) loci are molecular markers of parasite susceptibility to anti-malarial drugs. Their frequency distributions were determined in the isolates collected from children with severe malaria originating from three African countries.MethodsSamples from 287 children with severe malaria [(Gabon: n = 114); (Ghana: n = 89); (Kenya: n = 84)] were genotyped for pfmdr1, pfatp6 and pfk13 loci by DNA sequencing and assessing pfmdr1 copy number variation (CNV) by real-time PCR.ResultsPfmdr1-N86Y mutation was detected in 48, 10 and 10% in Lambaréné, Kumasi and Kisumu, respectively. At codon 184, the prevalence of the mutation was 73% in Lambaréné, 63% in Kumasi and 49% Kisumu. The S1034C and N1042D variants were absent at all three sites, while the frequency of the D1246Y mutation was 1, 3 and 13% in Lambaréné, Kumasi and Kisumu, respectively. Isolates with two pfmdr1 gene copy number predominantly harboured the N86Y wild-type allele and were mostly found in Kumasi (10%) (P < 0.0001). Among the main pfmdr1 haplotypes (NFD, NYD and YFD), NYD was associated with highest parasitaemia (P = 0.04). At the pfatp6 locus, H243Y and A623E mutations were observed at very low frequency at all three sites. The prevalence of the pfatp6 E431K variant was 6, 18 and 17% in Lambaréné, Kumasi and Kisumu, respectively. The L263E and S769N mutations were absent in all isolates. The pfk13 variants associated with artemisinin resistance in Southeast Asia were not observed. Eleven novel substitutions in the pfk13 locus occurring at low frequency were observed.ConclusionsArtemisinins are still highly efficacious in large malaria-endemic regions though declining efficacy has occurred in Southeast Asia. The return of chloroquine-sensitive strains following the removal of drug pressure is observed. However, selection of wild-type alleles in the multidrug-resistance gene and the increased gene copy number is associated with reduced lumefantrine sensitivity. This study indicates a need to constantly monitor drug resistance to artemisinin in field isolates from malaria-endemic countries.

【 授权许可】

CC BY   
© The Author(s) 2017